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Brostallicin

Brostallicin  is a synthetic, alpha-bromoacrylic, second-generation minor groove binder (MGB), related to distamycin A, with potential antineoplastic activity. Brostallicin binds to DNA minor groove DNA, after having formed a highly reactive glutathione (GSH)-brostallicin complex in the presence of the enzyme glutathione S-transferase (GST), which is overexpressed in cancer cells; DNA replication and cell division are inhibited, resulting in tumor cell death. Compared to typical MGBs, this agent appears to bind covalently to DNA in a different manner and its activity does not depend on a functional DNA mismatch repair (MMR) mechanism. Accordingly, brostallicin may be effective against MMR-defective tumors that are refractory to various anticancer agents. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Current developer:   

 1. Caponigro, F.; Lorusso, D.; Fornari, G.; Barone, C.; Merlano, M.; Airoldi, M.; Schena, M.; MacArthur, R.; Weitman, S.; Jannuzzo, M. G.; Crippa, S.; Fiorentini, F.; Petroccione, A.; Comis, S. Phase I dose-escalation study of brostallicin, a minor groove binder, in combination with cisplatin in patients with advanced solid tumors. Cancer Chemotherapy and Pharmacology (2010), 66(2), 389-394. CODEN: CCPHDZ ISSN:0344-5704. AN 2010:622626

2. Pezzola, Silvia; Antonini, Giovanni; Geroni, Cristina; Beria, Italo; Colombo, Maristella; Broggini, Massimo; Marchini, Sergio; Mongelli, Nicola; Leboffe, Loris; MacArthur, Robert; Mozzi, Alessia Francesca; Federici, Giorgio; Caccuri, Anna Maria. Correction to Role of Glutathione Transferases in the Mechanism of Brostallicin Activation. Biochemistry (2010), 49(23), 4930. CODEN: BICHAW ISSN:0006-2960. AN 2010:618736

3. Rickles, Richard; Lee, Margaret S.  -Adrenergic receptor agonists for the treatment of B-cell proliferative disorders. PCT Int. Appl. (2009), 111 pp. CODEN: PIXXD2 WO 2009151569 A2 20091217 CAN 152:67621 AN 2009:1566750

4. Pezzola, Silvia; Antonini, Giovanni; Geroni, Cristina; Beria, Italo; Colombo, Maristella; Broggini, Massimo; Mongelli, Nicola; Leboffe, Loris; MacArthur, Robert; Mozzi, Alessia Francesca; Federici, Giorgio; Caccuri, Anna Maria. Role of Glutathione Transferases in the Mechanism of Brostallicin Activation. Biochemistry (2010), 49(1), 226-235. CODEN: BICHAW ISSN:0006-2960. CAN 152:111089 AN 2009:1537627

5. Lorusso, Domenica; Mainenti, Sara; Pietragalla, Antonella; Ferrandina, Gabriella; Foco, Gilda; Masciullo, Valeria; Scambia, Giovanni. Brostallicin (PNU-166196), a new minor groove DNA binder: preclinical and clinical activity. Expert Opinion on Investigational Drugs (2009), 18(12), 1939-1946. CODEN: EOIDER ISSN:1354-3784. CAN 152:110619 AN 2009:1472481

6. Bruckheimer, Elizabeth; Kiefer, Jeff; Mousses, Spyro; Shanmugam, Kandavel; Yin, Hongwei; Weitman, Steve. Target expression-based method for assessing sensitivity to brostallicin. PCT Int. Appl. (2009), 66pp. CODEN: PIXXD2 WO 2009126970 A1 20091015 CAN 151:440645 AN 2009:1262339

7. Romagnoli, Romeo; Baraldi, Pier Giovanni; Cruz-Lopez, Olga; Preti, Delia; Bermejo, Jaime; Estevez, Francisco.  -Bromoacrylamido N-Substituted Isatin Derivatives as Potent Inducers of Apoptosis in Human Myeloid Leukemia Cells. ChemMedChem (2009), 4(10), 1668-1676. CODEN: CHEMGX ISSN:1860-7179. CAN 152:51175 AN 2009:1215039

8. Guirouilh-Barbat, Josee; Zhang, Yong-Wei; Pommier, Yves. Induction of glutathione-dependent DNA double-strand breaks by the novel anticancer drug brostallicin. Molecular Cancer Therapeutics (2009), 8(7), 1985-1994. CODEN: MCTOCF ISSN:1535-7163. CAN 151:279230 AN 2009:848543

9. Romagnoli, Romeo; Baraldi, Pier Giovanni; Cruz-Lopez, Olga; Lopez-Cara, Carlota; Preti, Delia.  -halogenoacrylic derivatives of antitumor agents. Mini-Reviews in Medicinal Chemistry (2009), 9(1), 81-94. CODEN: MMCIAE ISSN:1389-5575. CAN 151:310 AN 2009:460861

10. Rickles, Richard; Lee, Margaret S. Use of adenosine A2A receptor agonists and phosphodiesterase (PDE) inhibitors for the treatment of B-cell proliferative disorders, and combinations with other agents. PCT Int. Appl. (2009), 70 pp. CODEN: PIXXD2 WO 2009011893 A2 20090122 CAN 150:160095 AN 2009:86451

11. Rickles, Richard; Pierce, Laura; Lee, Margaret S. Combinations for the treatment of B-cell proliferative disorders. PCT Int. Appl. (2009), 79pp. CODEN: PIXXD2 WO 2009011897 A1 20090122 CAN 150:160094 AN 2009:83374

12. Amir, Eitan; Griffiths, Richard W.; Leahy, Michael G. Brostallicin hydrochloride: Minor groove-binding agent oncolytic. Drugs of the Future (2008), 33(6), 478-488. CODEN: DRFUD4 ISSN:0377-8282. CAN 150:159129 AN 2008:985291

13. Kasper, Bernd. Standards and novel therapeutic options in the treatment of patients with soft tissue sarcoma. Reviews on Recent Clinical Trials (2007), 2(3), 206-211. CODEN: RRCTB2 ISSN:1574-8871. CAN 148:141 AN 2007:1159760

14. Crivori, Patrizia; Morelli, Amedea; Pezzetta, Daniele; Rocchetti, Maurizio; Poggesi, Italo. Development and validation of in silico models for estimating drug preformulation risk in PEG400/water and Tween80/water systems. European Journal of Pharmaceutical Sciences (2007), 32(3), 169-181. CODEN: EPSCED ISSN:0928-0987. CAN 147:491351 AN 2007:1157669

15. Habib, Nabil. Treatment of cancer and other diseases. PCT Int. Appl. (2007), 86pp. CODEN: PIXXD2 WO 2007064691 A1 20070607 CAN 147:46112 AN 2007:619578

16. Hartmann, Joerg T. Systemic treatment options for patients with refractory adult-type sarcoma beyond anthracyclines. Anti-Cancer Drugs (2007), 18(3), 245-254. CODEN: ANTDEV ISSN:0959-4973. CAN 146:265555 AN 2007:105120

17. Leahy, Michael; Ray-Coquard, Isabelle; Verweij, Jaap; Le Cesne, Axel; Duffaud, Florence; Hogendoorn, Pancras C. W.; Fowst, Camilla; de Balincourt, Christine; Donato di Paola, Eugenio; van Glabbeke, Martine; Judson, Ian; Blay, Jean-Yves. Brostallicin, an agent with potential activity in metastatic soft tissue sarcoma: a phase II study from the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. European Journal of Cancer (2007), 43(2), 308-315. CODEN: EJCAEL ISSN:0959-8049. CAN 146:454375 AN 2007:98684

18. Michelson, Glenn C.; Chan, Vivien W.; Heise, Carla C.; Wiesmann, Marion; Dawes, Timothy D. Methods for treating drug resistant cancer. PCT Int. Appl. (2006), 151pp. CODEN: PIXXD2 WO 2006124413 A2 20061123 CAN 146:722 AN 2006:1225966

19. Valentini, Anna Maria; Armentano, Raffaele; Pirrelli, Michele; Caruso, Maria L. Chemotherapeutic agents for colorectal cancer with a defective mismatch repair system: the state of the art. Cancer Treatment Reviews (2006), 32(8), 607-618. CODEN: CTREDJ ISSN:0305-7372. CAN 146:175837 AN 2006:1166060

20. Scovassi, A. I.; Gorrini, C.; Pastori, W.; Ciomei, M. Analysis of brostallicin effect on different human gastrointestinal cancer cell lines. Letters in Drug Design & Discovery (2006), 3(8), 524-527. CODEN: LDDDAW ISSN:1570-1808. CAN 145:327935 AN 2006:1025254

21. Pook, Sim-Hwee; Toh, Chee-Keong; Mahendran, Ratha. Combination of thiol antioxidant Silibinin with Brostallicin is associated with increase in the anti-apoptotic protein Bcl-2 and decrease in caspase 3 activity. Cancer Letters (Amsterdam, Netherlands) (2006), 238(1), 146-152. CODEN: CALEDQ ISSN:0304-3835. CAN 145:159740 AN 2006:557242

22. Yaffe, Michael B.; Clapperton, Julie A.; Manke, Isaac A.; Lowery, Drew M.; Ho, Timmy; Haire, Lesley F.; Smerdon, Stephen J. The x-ray crystal structure of BRCA1 tandem BRCT repeat and BACH1 phosphopeptide complex and methods and compositions for antitumor drug design. PCT Int. Appl. (2005), 360 pp. CODEN: PIXXD2 WO 2005115454 A2 20051208 CAN 144:46998 AN 2005:1290072

23. Damia, Giovanna; Broggini, Massimo. DNA minor groove binding agents. Drugs of the Future (2005), 30(3), 301-309. CODEN: DRFUD4 ISSN:0377-8282. CAN 143:108824 AN 2005:563130

24. Lacasse, Eric; McManus, Daniel. Human protein IAP (inhibitor of apoptosis protein) nucleobase oligomers, including dsRNA, shRNA, and siRNA, and their use for enhancing apoptosis in cancer therapy. PCT Int. Appl. (2005), 112 pp. CODEN: PIXXD2 WO 2005042558 A1 20050512 CAN 142:457053 AN 2005:409543

25. Lacasse, Eric; McManus, Daniel; Durkin, Jon P. Sequences of antisense IAP (inhibitor of apoptosis protein) oligomers and their use for treatment of proliferative diseases with a chemotherapeutic agent. PCT Int. Appl. (2005), 285 pp. CODEN: PIXXD2 WO 2005042030 A1 20050512 CAN 142:457052 AN 2005:409357

26. Lee, Margaret S.; Nichols, James M.; Zhang, Yanzhen; Keith, Curtis. Combinations of chlorpromazine compounds and antiproliferative drugs for the treatment of neoplasms. PCT Int. Appl. (2005), 65 pp. CODEN: PIXXD2 WO 2005027842 A2 20050331 CAN 142:349042 AN 2005:283298

27. Hartmann, Joerg Thomas; Patel, Shreyaskumar. Recent developments in salvage chemotherapy for patients with metastatic soft tissue sarcoma. Drugs (2005), 65(2), 167-178. CODEN: DRUGAY ISSN:0012-6667. CAN 142:456070 AN 2005:153796

28. Geroni, Maria Cristina; Fowst, Camilla; Broggini, Massimo. Use of bromo- or chloro-substituted acrylolyl distamycin derivatives in combination with demethylating agents, in the treatment of cancer. PCT Int. Appl. (2004), 19 pp. CODEN: PIXXD2 WO 2004035045 A1 20040429 CAN 140:368652 AN 2004:354786

29. Broggini, Massimo; Marchini, Sergio; Fontana, Erminia; Moneta, Donatella; Fowst, Camilla; Geroni, Cristina. Brostallicin: a new concept in minor groove DNA binder development. Anti-Cancer Drugs (2004), 15(1), 1-6. CODEN: ANTDEV ISSN:0959-4973. CAN 140:314311 AN 2004:302992

30. Beria, Italo; Baraldi, Pier Giovanni; Cozzi, Paolo; Caldarelli, Marina; Geroni, Cristina; Marchini, Sergio; Mongelli, Nicola; Romagnoli, Romeo. Cytotoxic  -Halogenoacrylic Derivatives of Distamycin A and Congeners. Journal of Medicinal Chemistry (2004), 47(10), 2611-2623. CODEN: JMCMAR ISSN:0022-2623. CAN 141:23889 AN 2004:279155

31. Lockhart, A. Craig; Howard, Martin; Hande, Kenneth R.; Roth, Bruce J.; Berlin, Jordan D.; Vreeland, Franzanne; Campbell, Angela; Fontana, Erminia; Fiorentini, Francesca; Fowst, Camilla; Paty, Victoria A.; Lankford, Odessa; Rothenberg, Mace L. A Phase I dose-escalation and pharmacokinetic study of brostallicin (PNU-166196A), a novel DNA minor groove binder, in adult patients with advanced solid tumors. Clinical Cancer Research (2004), 10(2), 468-475. CODEN: CCREF4 ISSN:1078-0432. CAN 141:218249 AN 2004:88580

32. Sabatino, Maria Antonietta; Colombo, Tina; Geroni, Cristina; Marchini, Sergio; Broggini, Massimo. Enhancement of in Vivo Antitumor Activity of Classical Anticancer Agents by Combination with the New, Glutathione-Interacting DNA Minor Groove-Binder, Brostallicin. Clinical Cancer Research (2003), 9(14), 5402-5408. CODEN: CCREF4 ISSN:1078-0432. CAN 140:399441 AN 2003:887412

33. Fedier, A.; Fowst, C.; Tursi, J.; Geroni, C.; Haller, U.; Marchini, S.; Fink, D. Brostallicin (PNU-166196) - a new DNA minor groove binder that retains sensitivity in DNA mismatch repair-deficient tumour cells. British Journal of Cancer (2003), 89(8), 1559-1565. CODEN: BJCAAI ISSN:0007-0920. CAN 140:368193 AN 2003:813739

34. Geroni, Maria Cristina Rosa; Tursi, Jennifer Margaret; Fowst, Camilla. Combined therapy against tumors comprising substituted acryloyl distamycin derivatives and radiotherapy. PCT Int. Appl. (2003), 17 pp. CODEN: PIXXD2 WO 2003082267 A1 20031009 CAN 139:286329 AN 2003:796472

35. Cammia, Cristiano; De Nicolao, Giuseppe; Poggesi, Italo; Rocchetti, Maurizio. Method for estimating or predicting the antitumor activity of a compound and for estimating or predicting the tumor growth in mammals. PCT Int. Appl. (2003), 85 pp. CODEN: PIXXD2 WO 2003079004 A2 20030925 CAN 139:255340 AN 2003:757951

36. ten Tije, Albert J.; Verweij, Jaap; Sparreboom, Alex; van der Gaast, Ate; Fowst, Camilla; Fiorentini, Francesco; Tursi, Jennifer; Antonellini, Alessandro; Mantel, Marijke; Hartman, Carla M.; Stoter, Gerrit; Planting, Andre S. T.; de Jonge, Maja J. A. Phase I and Pharmacokinetic Study of Brostallicin (PNU-166196), a New DNA Minor-Groove Binder, Administered Intravenously Every 3 Weeks to Adult Patients with Metastatic Cancer. Clinical Cancer Research (2003), 9(8), 2957-2964. CODEN: CCREF4 ISSN:1078-0432. CAN 140:122216 AN 2003:619200

37. Calderoli, Sara; Colombo, Emiliana; Frigerio, Enrico; James, Christopher A.; Sibum, Martin. LC-MS-MS determination of brostallicin in human plasma following automated on-line SPE. Journal of Pharmaceutical and Biomedical Analysis (2003), 32(4-5), 601-607. CODEN: JPBADA ISSN:0731-7085. CAN 139:301208 AN 2003:598249

38. Geroni, Maria Cristina; Fowst, Camilla; Cozzi, Paolo. Combined therapy against tumors comprising substituted acryloyl distamycin derivatives and protein kinase (serine/threonine kinase) inhibitors. PCT Int. Appl. (2003), 25 pp. CODEN: PIXXD2 WO 2003055522 A1 20030710 CAN 139:95455 AN 2003:532545

39. Fowst, Camilla; Geroni, Maria Cristina Rosa; Tursi, Jennifer Margaret; Vreeland, Franzanne. Method using glutathione blood level for predicting the sensitivity to chemotherapy. PCT Int. Appl. (2003), 16 pp. CODEN: PIXXD2 WO 2003029825 A2 20030410 CAN 138:281106 AN 2003:282836

40. Cozzi, Paolo. The discovery of a new potential anticancer drug: a case history. Farmaco (2003), 58(3), 213-220. CODEN: FRMCE8 ISSN:0014-827X. CAN 139:190798 AN 2003:164766

41. Baker, Sharyn D.; Verweij, Jaap; Rowinsky, Eric K.; Donehower, Ross C.; Schellens, Jan H. M.; Grochow, Louise B.; Sparreboom, Alex. Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001. Journal of the National Cancer Institute (2002), 94(24), 1883-1888. CODEN: JNCIEQ ISSN:0027-8874. CAN 139:223633 AN 2003:55812

42. Fontana, E.; Pignatti, A. Synthesis of brostallicin (PNU-166196A) labelled with 2H and 14C. Journal of Labelled Compounds & Radiopharmaceuticals (2002), 45(11), 899-909. CODEN: JLCRD4 ISSN:0362-4803. CAN 138:304112 AN 2002:903490

43. Beria, Italo; Nesi, Marcella. Syntheses of brostallicin starting from distamycin A. Tetrahedron Letters (2002), 43(41), 7323-7327. CODEN: TELEAY ISSN:0040-4039. CAN 138:137576 AN 2002:818383

44. Caldarelli, Francesco; Ceriani, Lucio; Candiani, Ilaria. Process for preparing distamycin derivatives. PCT Int. Appl. (2002), 22 pp. CODEN: PIXXD2 WO 2002044147 A1 20020606 CAN 136:402031 AN 2002:428876

45. Beria, Italo; Caldarelli, Marina; Geroni, Cristina; Mongelli, Nicola; Reinach, Benedetta; Vignati, Luisella; Cozzi, Paolo. Cytotoxic alpha-Bromoacrylic derivatives of low molecular weight. Bioorganic & Medicinal Chemistry Letters (2002), 12(11), 1467-1471. CODEN: BMCLE8 ISSN:0960-894X. CAN 138:19111 AN 2002:379634

46. Geroni, Cristina; Marchini, Sergio; Cozzi, Paolo; Galliera, Emanuela; Ragg, Enzio; Colombo, Tina; Battaglia, Rosangela; Howard, Martin; D'Incalci, Maurizio; Broggini, Massimo. Brostallicin, a novel anticancer agent whose activity is enhanced upon binding to glutathione. Cancer Research (2002), 62(8), 2332-2336. CODEN: CNREA8 ISSN:0008-5472. CAN 137:195148 AN 2002:323080

47. Fowst, Camilla; Vreeland, Franzanne; Geroni, Maria Cristina Rosa. Antitumor therapy comprising distamycin derivatives. PCT Int. Appl. (2002), 13 pp. CODEN: PIXXD2 WO 2002028389 A1 20020411 CAN 136:304046 AN 2002:275788

48. Beria, Italo; Cozzi, Paolo; Mongelli, Nicola; Nesi, Marcella. Preparation of distamycin derivatives as intermediates for synthesis of distamycin antitumor agents. PCT Int. Appl. (2002), 30 pp. CODEN: PIXXD2 WO 2002008184 A1 20020131 CAN 136:135030 AN 2002:90004

49. Beria, Italo; Cozzi, Paolo; Mongelli, Nicola; Orzi, Fabrizio. Process for preparation of distamycin peptidic derivatives as antitumor agents. PCT Int. Appl. (2002), 32 pp. CODEN: PIXXD2 WO 2002002523 A1 20020110 CAN 136:86055 AN 2002:31413

50. Geroni, Maria Cristina Rosa; Cozzi, Paolo; Beria, Italo. Combined therapy against tumors comprising substituted acryloyl distamycin derivatives and alkylating agents. PCT Int. Appl. (2001), 19 pp. CODEN: PIXXD2 WO 2001097790 A2 20011227 CAN 136:64106 AN 2001:935388